Synthesis of imidazo [1,2-a] pyridine and pyrazolo [1,5-a] pyridine derivatives as potential kinase inhibitors (PvPI4K and PfPKG) of plasmodiumfalciparum parasite

Abstract

5-Amino-3-iodopyrazolo[1,5-a]pyridine was prepared via the iodination of commercially available 5-aminopyrazolo[1,5-a]pyridine in the presence of N-iodosuccinimide (NIS) in methanol. Palladium catalyzed Suzuki-Miyaura cross-coupling reaction on the 5-amino-3-iodopyrazolo[1,5-a]pyridine with arylboronic acids in dioxane-water afforded the 3-aryl substituted pyrazolo[1,5-a]pyridin-5-amine derivative, which were in turn, subjected to Sandmeyer reaction in the presence of concentrated hydrobromic acid, copper (ii) bromide and NaNO2 to afforded the desired 5-bromo-3-(4 (methylsulfonyl)phenyl)pyrazolo[1,5-a]pyridine in 70% yield. Subsequent Suzuki-Miyaura cross-coupling on the 5-bromo-3-(4-(methylsulfonyl)phenyl)pyrazolo[1,5-a]pyridine with various arylboronic acids afforded two compounds of the 3,5-substituted pyrazolo[1,5-a]pyridine derivatives in 47% and 53% yield. Condensation of 5-chloropyridin-2-amine and 2-chloroacetaldehyde in ethanol afforded 6-chloro imidazo[1,2-a]pyridine, which was in turn, treated with NIS in DMF to afford 6-chloro-3-iodo imidazo[1,2-a]pyridine in 71% yield. Sequential, palladium catalyzed Suzuki-Miyaura cross-coupling reaction on the latter with numerous boronic acids afforded 20 compounds of the desired 3,6-substituted imidazo[1,2-a]pyridine derivatives in 47-80% yield. The prepared compounds were characterized using a combination of NMR (1H and 13C) and mass spectrometric techniques. The compounds’ antimalarial properties were investigated against Plasmodium falciparum and inhibitory studies were conducted against the PvPI4k and PfPKG kinases and some bioactive derivatives were further subjected to molecular docking studies. The enzymatic data displayed moderate anti-plasmodium activity for compound 40b with IC50 values of PfNF54/ PfK1 (IC50 = 0.3709 μM/ 0.6447 μM ) and in vitro PfPKG/ PvPI4K inhibitory activities (IC50 = 2.210/ 0.032 μM).